1. What every clinician should know Are you sure your patient has disease? What should you expect to find?

Cervical Intraepithelial Neoplasia (CIN) or cervical dysplasia is a premalignant condition of the cervix caused by the Human Papilloma Virus (HPV) and usually detected by screening with cytology (Pap test) and/or HPV testing. If left untreated, CIN can develop into invasive cervical cancer.

There are three categories of CIN based on histological changes:

CIN 1 includes mild dysplasia and condyloma (anogenital warts)

CIN 2 includes moderate dysplasia

CIN 3 includes severe dysplasia and carcinoma-in-situ (CIS)

CIN is graded based on the extent of abnormal cell proliferation of the basal layer of the cervical epithelium. CIN 1 is considered a low-grade lesion, and CIN 2 and 3 are considered high-grade lesions. In CIN 1, proliferation occurs up to the lower third of the epithelium. In CIN 2, proliferation occurs up to the upper two thirds, and in CIN 3, proliferation occurs in the upper two thirds of the epithelium. In CIS, the entire epithelium is abnormal.

CIN and cervical cancer are caused by the sexually transmitted Human Papilloma Virus (HPV). The initial infection usually occurs during adolescence, and up to 80% of women are infected with HPV at some point during their lifetime. The majority of HPV infections clear without treatment, but in some patients the infection persists and can develop into CIN or possibly cancer.

HPV is central to the pathogenesis of cervical cancer, with the virus detected in over 99% of cases. Furthermore, HPV has also been associated with other malignancies, including cancer of the vulva, vagina, anus, oropharynx, and penis. To date, more than 100 HPV subtypes have been identified, approximately 40 of which are associated with anogential infections, and these include both low-risk and high-risk subtypes. The most common low-risk subtypes are HPV 6 and 11, which account for more than 90% of cases of anogential condyloma or genital warts. HPV 16 and 18 are the most common high-risk subtypes and account for 70% of cervical cancer cases. Prophylactic vaccines are currently available to protect against HPV (see the chapter on prophylatic vaccinations).

HPV infection is necessary but not sufficient to develop CIN. More than 90% of infections are spontaneously cleared by the immune system within one year without treatment. Approximately 60% of CIN 1 lesions regress without treatment and less than 1% progress to cancer. However, it is estimated that 5% of CIN 2 and 12% of CIN 3 cases will progress to invasive cancer if untreated. In general, it takes 10 to 20 years for CIN to progress to cancer, allowing a significant time period for detection and treatment. Progression from CIN to cancer requires persistent HPV infection.

Co-factors associated with persistent HPV infection and progression of disease include smoking, HIV infection, and other types of immunosuppression.Cervical cancer is the 14 th most common cancer among women in the United States. There are approximately 12,710 new cases and 4,290 cervical cancer related deaths per year. However, 85% of cervical cancer cases in the world occur in developing countries due to a lack of screening programs. Cervical cancer is therefore the second most common cause of cancer death among women worldwide, with over 400,000 preventable deaths occurring per year.

In the United States, 3.5 million (7%) of the 50 million Pap tests performed each year are abnormal and require additional testing. Approximately 300,000 of these women are subsequently diagnosed with CIN 2 or 3. The cost associated with the diagnosis and treatment of cervical dysplasia and genital warts in the United States is estimated to be 3 billion dollars per year.

The risk factors for CIN are the same as the risk factors for HPV infection and cervical cancer. They include:

CIN 2 and 3 is usually asymptomatic and diagnosed following an abnormal screening Pap and/or HPV test. CIN 1 can be associated with the development of anogenital warts/condyloma

2. Diagnosis and differential diagnosis

CIN is diagnosed by colposcopic-directed cervical biopsies. In the Unites States, cervical cancer screening includes cytology using the Pap test, often in combination with HPV testing for high-risk subtypes. Current guidelines recommend initiating cervical cancer screening with cytology at age 21 and to repeat every two years between the ages of 21 and 29. For women age 30 to 65 years, Pap and HPV testing is recommended every 5 years. Cervical cancer screening is discontinued at age 65 if the patient has no history of abnormal screening for the last 10 years.

Women with abnormal screening results are referred for colposcopy, a diagnostic procedure using a colposcope to provide an illuminated, magnified view of the cervix after applying 3-5% acetic acid. Dysplastic cells reflect light and appear white on colposcopic exam. These areas are further evaluated for abnormal vascular patterns including punctation, mosaicism, or abnormal appearing vessels. Abnormal appearing areas are biopsied.

Screening for cervical cancer in low resource settings

Cervical cancer is the leading cause of death from cancer among women in the developing world. Current screening methods using cervical cytology, HPV testing, and colposcopy require up to three visits with communication of results between each visit. This strategy is often not feasible in developing settings due to economic and infrastructure limitations.

"Screen and Treat" protocols, in which a screening test is followed in the same visit by treatment of women with positive results, eliminate these communication difficulties as well as the issue of noncompliance with follow-up. An accepted strategy includes visual inspection with acetic acid (VIA) immediately followed by ablative treatment with cryotherapy for women with positive results. A potential future option is a rapid result HPV test, with several types currently under development.

3. Management

A. What should the initial definitive therapy for the cancer be?

Consensus guidelines for the management and follow-up of patients with CIN are provided by the American Society for Colposcopy and Cervical Pathology (ASCCP) and updated regularly (www.ASCCP.org).

How is CIN 1 managed?

CIN 1 with low-grade cervical cytology

Given the high rates of spontaneous regression, CIN 1 is usually managed expectantly. This is particularly true if the diagnosis of CIN 1 is preceded by low grade cervical cytology, i.e., ASC-US or LSIL. These patients can undergo repeat cytoloty and HPV testing (co-testing) at 12 months.

CIN 1 with high-grade cervical cytology

If the diagnosis of CIN 1 is preceded by cytology showing HSIL, there is a higher chance of underlying CIN 2/3 or worse, and more aggressive management is considered. In patients who have completed childbearing, an excisional procedure is recommended. In women who desire future fertility, close follow-up with cytology and HPV testing (co-testing) at 12 months is performed.

How is CIN 2 & 3 managed?

Given the lower rates of spontaneous regression and higher rates of progression, it is recommended that most women with CIN 2 or CIN 3 undergo treatment. Both ablative and excisional procedures are used, with similar efficacy rates (>90% cure) in properly selected patients.

Ablative procedures

Ablative procedures are solely for the treatment of CIN and do not provide further diagnostic information. To qualify for ablative therapy, there should be no suspicion of glandular or invasive squamous disease. Specific criteria for ablative therapies include:

Biopsy confirming presence of CIN, as abnormal cytology alone is not sufficient

Negative endocervical curettage

The most common ablative procedures used in the United States are cryotherapy and laser ablation. Both procedures are effective with limited adverse effects.

Cryotherapy

Cryotherapy cools the ectocervix with a metal cryoprobe using a refrigerant gas - either carbon dioxide or nitrous oxide. The ectocervix is cooled to -20ºC, causing crystallization of intracellular water that destroys the lesion. A freeze-thaw-freeze cycle is used where the cervix is frozen for three minutes, allowed to thaw, and then frozen again for three minutes. Cryotherapy can be performed in the office setting by trained nurses or paramedical staff.

Laser ablation

Laser ablation of CIN can be performed by physicians with specialized training. A carbon dioxide laser is directed at the cervical lesion under colposcopic guidance. Water in the tissue absorbs the laser energy, and the tissue is destroyed by vaporization. The lesion is typically ablated to a depth of 5 mm on the ectocervix and 8-9 mm around the endocervix. Several safety procedures must be followed, including the use of protective eyewear by all personnel in the procedure room, the use of a blackened or brushed speculum to avoid damage to surrounding tissues by misdirected laser beams, and using wet towels and cloth drapes to prevent fires.

Excisional procedures

Excisional procedures have the advantage over ablative procedures of providing a specimen for further diagnostic information. The specific indications over ablative procedures include:

Suspected microinvasion

Unsatisfactory colposcopy (the transformation zone is not fully visualized)

Lesion extending into the endocervical canal

Endocervical curettage showing CIN or a glandular abnormality

Lack of correlation between the cytology and colposcopy/biopsies

Suspected adenocarcinoma in situ

Unable to rule out invasive disease

Recurrence after an ablative or previous excisional procedure

The most common procedures used in the United States include cold knife conization (CKC), laser conization, and loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ). In both procedures, the cervix is infiltrated with an anesthetic/vasoconstrictor solution and a cone shaped piece of the cervix inclusive of the transformation zone is removed. This may be followed by an endocervical curretage (ECC) above the cone bed. There is no evidence that one technique is significantly more effective than the other.

Cold knife conization

Cold knife conization (CKC) is performed with a scalpel under general or regional anesthesia in the operating room. CKC is recommended in patients with suspected microinvasion or adenocarcinoma in situ (AIS), as the margins can be evaluated without cautery artifact.

Laser conization

Laser conization uses a carbon dioxide laser to excise a cone-shaped piece of the cervix. It is usually performed in the operating room under general or regional anesthesia.

LEEP/LLETZ

The LEEP or LLETZ procedure utilizes a thin wire in the shape of a loop with an electrosurgical generator. The loops are available in a variety of shapes and sizes, allowing individualization of the cone specimen removed in order to avoid excessive excision. This procedure has the advantage of being performed in the office setting. However, there may be difficulty in evaluating the specimen margins due to thermal artifact.

4. Complications

A. What complications could arise as a consequence of the management – chemo, radiation, and surgical?

What are the complications of ablative procedures?

Women undergoing cryotherapy may experience watery vaginal discharge for several weeks after treatment. If patients find the discharge bothersome, the necrotic tissue can be removed from the cervix using ring forceps. There is a small risk of vaginal bleeding and pelvic infection following either laser ablation or cryotherapy. The rate of cervical stenosis for both procedures is less than 1%.

What are the complications of excisional procedures?

CKC, laser conization, and LEEP/LLETZ may be complicated by bleeding during or following the procedure. Bleeding is rarely heavy, and conservative measures using cautery, sutures, or ferric subsulfate paste (Monsel's solution) are usually adequate for control of hemorrhage. The incidence of infection is 0.2-6.8% following CKC and <2% following laser conization or LEEP/LLETZ. Routine prophylactic antibiotic use is not recommended for any of the ablative or excisional procedures.

What are the effects of ablative and excisional procedures on fertility and pregnancy?

Excisional and ablative procedures for CIN are often performed in reproductive age women and may impact future fertility and pregnancy outcomes. Cervical stenosis following excisional procedures has been reported in up to 8% of patients, however it is particularly post menopausal women with a large amount of tissue removed. In comparison, cervical stenosis occurs in <1% of patients undergoing ablative procedures. Furthermore, excisional procedures, particularly CKC, are associated with an increased risk of second trimester pregnancy loss and preterm delivery compared with ablative procedures.

Women who are planning future pregnancy should be treated with the method that best diagnoses or treats CIN, yet incurs the lowest risk of adverse effects on fertility. If an excisional procedure is performed, an interval of at least three months is recommended prior to becoming pregnant.

5.Prognosis and outcome

A. What would you tell patient and family about the prognosis?

What is the risk of recurrence following treatment of CIN 2/3?

The rate of recurrent or persistent disease is 5-17% following excisional or ablative treatment for CIN 2 or 3. There are no significant differences in efficacy between the different treatment modalities described. Factors associated with recurrent/persistent disease include:

Large lesion size (i.e., greater than two-thirds the surface of the cervix)

Endocervical gland involvement

Positive margins

Patients who have positive margins on the excised specimens or in the concomitant ECC specimen can undergo a repeat excisional procedure or be followed closely with follow-up cytology, HPV testing, colposcopy and/or ECC.

B. "What if" scenarios

What is the treatment for adenocarcinoma in situ (AIS) of the cervix?

Adenocarcinoma in situ (AIS) of the cervix is a premalignant glandular condition and the only known precursor to cervical adenocarcinoma. Most lesions are contiguous, but 10-15% of patients with AIS have multifocal disease with “skip” lesions. In women with known or suspected AIS, cervical conization is recommended to make or confirm the diagnosis, assess the extent of disease, exclude invasive disease, and exclude a coexistent squamous lesion.

CKC is preferred over LEEP/LLETZ in order to adequately assess the margins. If positive margins are noted on the cone specimen, a repeat CKC is recommended. Given the possibility of skip lesions, hysterectomy is recommended for women with AIS who have completed childbearing. Close follow-up is acceptable for women who desire future fertility and have negative cone margins.

How should adolescents with CIN 2/3 be managed?

In females 24 years of age or younger, the rate of regression of CIN2/3 is high and progression to invasive cancer is rare. These patients can undergo close observation rather than ablative or excisional procedures. This includes cytology and colposcopy at 6 and 12 months.

How should CIN 2/3 be managed in pregnancy?

The treatment of CIN 2/3 should be avoided during pregnancy due to the high rates of regression postpartum and the significant morbidity associated with cervical conization in pregnancy. Patients should undergo repeat cytology, HPV testing and colposcopy 6-12 weeks postpartum. Endocervical curettage should never be performed during pregnancy.

6. Follow up surveillance and therapy management of recurrences

Surveillance following ablation or excision for CIN 2 or 3 consists of co-testing with cytology and HPV testing at 12 months consists of co-testing with cytology and HPV testing at 12 months.

Patients can return to annual screening once they ahve both a negative cervical cytology and HPV test, or two consecutive negative tests. Women diagnosed with CIN 2 or 3 require annual surveillance for 20 years.

7. What is the evidence for specific management and treatment recommendations?